Clinical Trials: More than 12,000 patients have been treated with VIREAD alone or in combination with other antiretroviral medicinal products for periods of 28 days to 215 weeks in Phase I–III clinical trials and expanded access studies. A total of 1,544 patients have received VIREAD 300 mg once daily in Phase I–III clinical trials; over 11,000 patients have received VIREAD in expanded access studies.

Treatment-Naïve Patients

Study 903 - Treatment-Emergent Adverse Events: The most common adverse reactions seen in a double-blind comparative controlled study in which 600 treatment-naïve patients received VIREAD (N=299) or stavudine (N=301) in combination with lamivudine and efavirenz for 144 weeks (Study 903) were mild to moderate gastrointestinal events and dizziness.

Mild adverse events (Grade 1) were common with a similar incidence in both arms, and included dizziness, diarrhea, and nausea. Selected treatment-emergent moderate to severe adverse events are summarized in Table 9.

Table 9: Selected Treatment-Emergent Adverse Events (Grades 2–4) Reported in ≥ 5% in Any Treatment Group in Study 903 (0–144 Weeks)

Laboratory Abnormalities: With the exception of fasting cholesterol and fasting triglyceride elevations that were more common in the stavudine group (40% and 9%) compared with VIREAD (19% and 1%) respectively, laboratory abnormalities observed in this study occurred with similar frequency in the VIREAD and stavudine treatment arms. A summary of Grade 3 and 4 laboratory abnormalities is provided in Table 10.

Table 10: Grade 3/4 Laboratory Abnormalities Reported in ≥ 1% of VIREAD-Treated Patients in Study 903 (0–144 Weeks)

Study 934 - Treatment Emergent Adverse Events: InStudy 934, 511 antiretroviral-naïve patients received either VIREAD + EMTRIVA administered in combination with efavirenz (N=257) or zidovudine/lamivudine administered in combination with efavirenz (N=254). Adverse events observed in this study were generally consistent with those seen in previous studies in treatment-experienced or treatment-naïve patients (Table 11).

Table 11: Selected Treatment-Emergent Adverse Events (Grades 2–4) Reported in ≥ 3% in Any Treatment Group in Study 934 (0–48 Weeks)

Laboratory Abnormalities: Laboratory abnormalities observed in this study were generally consistent with those seen in previous studies (Table 12).

Table 12: Significant Laboratory Abnormalities Reported in ≥ 1% of Patients in Any Treatment Group in Study 934 (0–48 Weeks)

Treatment-Experienced Patients

Treatment-Emergent Adverse Events: The adverse reactions seen in treatment experienced patients were generally consistent with those seen in treatment naïve patients including mild to moderate gastrointestinal events, such as nausea, diarrhea, vomiting, and flatulence. Less than 1% of patients discontinued participation in the clinical studies due to gastrointestinal adverse events (Study 907). A summary of moderate to severe, treatment-emergent adverse events that occurred during the first 48 weeks of Study 907 is provided in Table 13.

Table 13: Selected Treatment-Emergent Adverse Events (Grades 2–4) Reported in ≥ 3% in Any Treatment Group in Study 907 (0–48 Weeks)

Laboratory Abnormalities: Laboratory abnormalities observed in this study occurred with similar frequency in the VIREAD and placebo-treated groups. A summary of Grade 3 and 4 laboratory abnormalities is provided in Table 14.

Table 14: Grade 3/4 Laboratory Abnormalities Reported in ≥ 1% of VIREAD-Treated Patients in Study 907 (0–48 Weeks)

Post Marketing Experience: The following events have been identified during post-approval use of VIREAD. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting or potential causal connection to VIREAD.

IMMUNE SYSTEM DISORDERS
Allergic reaction

METABOLISM AND NUTRITION DISORDERS
Hypophosphatemia, Lactic acidosis

RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS
Dyspnea

GASTROINTESTINAL DISORDERS
Abdominal pain, Increased amylase, Pancreatitis

HEPATOBILIARY DISORDERS
Increased liver enzymes, Hepatitis

SKIN AND SUBCUTANEOUS TISSUE DISORDERS
Rash

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
Myopathy, Osteomalacia (both associated with proximal renal tubulopathy)

RENAL AND URINARY DISORDERS
Renal insufficiency, Renal failure, Acute renal failure, Fanconi syndrome, Proximal tubulopathy, Proteinuria, Increased creatinine, Acute tubular necrosis, Nephrogenic diabetes insipidus, Polyuria, Interstitial nephritis (including acute cases).

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
Asthenia

When administered with VIREAD, Cmax and AUC of didanosine (Videx, Videx EC) administered as either the buffered or enteric-coated formulation increased significantly (see Table 5). The mechanism of this interaction is unknown. Higher didanosine concentrations could potentiate didanosine-associated adverse events, including pancreatitis and neuropathy. Suppression of CD4 cell counts has been observed in patients receiving tenofovir DF with didanosine at a dose of 400 mg daily. In adults weighing > 60 kg, the didanosine dose should be reduced to 250 mg when it is coadministered with VIREAD. Data are not available to recommend a dose adjustment of didanosine for patients weighing < 60 kg. When coadministered, VIREAD and didanosine EC may be taken under fasted conditions or with a light meal ( < 400 kcal, 20% fat). Coadministration of didanosine buffered tablet formulation with VIREAD should be under fasted conditions.

Coadministration of VIREAD and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse events. Didanosine should be discontinued in patients who develop didanosine-associated adverse events.

Since tenofovir is primarily eliminated by the kidneys, coadministration of VIREAD with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of tenofovir and/or increase the concentrations of other renally eliminated drugs. Some examples include, but are not limited to adefovir dipivoxil, cidofovir, acyclovir, valacyclovir, ganciclovir, and valganciclovir.

Higher tenofovir concentrations could potentiate VIREAD-associated adverse events, including renal disorders.

Atazanavir and lopinavir/ritonavir have been shown to increase tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving atazanavir and lopinavir/ritonavir and VIREAD should be monitored for VIREAD-associated adverse events. VIREAD should be discontinued in patients who develop VIREAD-associated adverse events.

VIREAD decreases the AUC and Cmin of atazanavir. When coadministered with VIREAD, it is recommended that atazanavir 300 mg is given with ritonavir 100 mg. Atazanavir without ritonavir should not be coadministered with VIREAD.

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